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GABA A receptor
(nAchR: ) which is very similar to the GABAA receptor. Top: side view of the nAchR imbedded in a cell membrane. Bottom: view of the receptor from the extracellular face of the membrane. The subunits are labeled according to the GABAA nomenclature and the approximate locations of the GABA and benzodiazepine (BZ) binding sites are noted (between the α- and β-subunits and between the α- and γ-subunits respectively).]] (yellow lines connected to blue spheres). The four transmembrane α-helices (1-4) are depicted as cylinders. The disulfide bond in the C-terminal extracellular domain which is characteristic of the family of cys-loop receptors (which includes the GABAA receptor) is depicted as a yellow line. Right: Five subunits symmetrically arranged about the central chloride anion conduction pore. The extracellular loops are not depicted for the sake of clarity.]] The GABAA receptor is one of two ligand-gated ion channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. In addition to the GABA binding site, the GABAA receptor complex appears to have distinct allosteric binding sites for barbiturates, ethanol, inhaled anaesthetics, furosemide, GHB, kavalactones, neuroactive steroids, and picrotoxin. The GABAA receptor protein complex is also the molecular target of the benzodiazepine (BZ) class of tranquilizer drugs, and hence this complex is sometimes referred to as the benzodiazepine receptor (BzR). However benzodiazepines do not bind to the same receptor site on the protein complex as the endogenous ligand, GABA. Since the binding of some BZs is not specific to GABAA receptors and some GABAA receptors are insensitive to BZs, the IUPHAR has recommended that the name benzodiazepine receptor be replaced by BZ-sensitive GABAA receptor. Structure and function The receptor is a multimeric transmembrane receptor that consists of five subunits arranged around a central pore. The receptor sits in the membrane of its neuron at a synapse. The ligand GABA is the endogenous compound that causes this receptor to open; once bound to GABA, the protein receptor changes conformation within the membrane, opening the pore in order to allow chloride ions (Cl−) to pass down an electrochemical gradient. Because the reversal potential for chloride in most neurons is close to or more negative than the resting membrane potential, activation of GABAA receptors tends to stabilize the resting potential, and can make it more difficult for excitatory neurotransmitters to depolarize the neuron and generate an action potential. The net effect is typically inhibitory, reducing the activity of the neuron. The GABAA channel opens quickly and thus contributes to the early part of the inhibitory post-synaptic potential (IPSP). 1999. [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=bnchm.section.1181 Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Sixth Edition]. GABA Receptor Physiology and Pharmacology. . The endogenous ligand that binds to the benzodiazepine receptor is inosine. Subunits GABAA receptors are members of the large "Cys-loop" super-family of evolutionarily related and structurally similar ligand-gated ion channels that also includes nicotinic acetylcholine receptors, glycine receptors, and the 5HT3 receptor. There are numerous subunit isoforms for the GABAA receptor, which determine the receptor’s agonist affinity, chance of opening, conductance, and other properties. In humans, the units are as follows:Martin IL and Dunn SMJ. GABA receptors A review of GABA and the receptors to which it binds. Tocris Cookson LTD. * six types of α subunits (GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6) * three β's (GABRB1, GABRB2, GABRB3) * three γ's (GABRG1, GABRG2, GABRG3) * as well as a δ (GABRD), an ε (GABRE), a π (GABRP), and a θ (GABRQ) There are three ρ units (GABRR1, GABRR2, GABRR3), however these do not coassemble with the classical GABAA units listed above, but rather homooligomerize to form GABAC receptors. Five subunits can combine in different ways to form GABAA channels, but the most common type in the brain is a pentamer comprising two α's, two β's, and a γ (α2β2γ). The receptor binds two GABA molecules, at the interface between an α and a β subunit. Pharmacology Other ligands (besides GABA) interact with the GABAA receptor complex to increase chloride conductance (agonists), decrease conductance (inverse agonists) or to bind to the receptor and have no effect other than to prevent the binding of agonists or inverse agonists (antagonists). Hence ligands for the GABAA receptor span a range of effects from full agonism to antagonism to inverse agonism. Agonists Full agonists display a large number of effects including anti-anxiety (anxiolytic), muscle relaxant, sedation, anti-convulsion, and at high enough doses, anaesthesia. Partial agonists may display a subset of these properties (for example anxiolytic without sedation). Such other agonist ligands include * benzodiazepines (increase pore opening frequency; often the active ingredient of sleep pills and anxiety medications) * nonbenzodiazepines (newer class of sleep / anti-anxiety medications) * barbiturates (increase pore opening duration; used as sedatives) * kavalactones (psychoactive compounds found in the roots of the kava plant) * certain steroids, called neuroactive steroids Muscimol is an agonist used to distinguish GABAA from the GABAB receptor. Antagonists Among antagonists are * picrotoxin (non-competitive; binds the channel pore, effectively blocking any ions from moving through it) * bicuculline (competitive; transiently occupies the GABA binding site, thus preventing GABA from activating the receptor) * cicutoxin and oenanthotoxin, poisons found in certain Northern Hemisphere plants that grow in boggy soils. * flumazenil which is used medically to reverse excessive effects of the benzodiazepines. Inverse agonists Full inverse agonists such as DMCM have anxiogenic and convulsant properties, while partial inverse agonists may be useful as aids in memory and learning and as antidotes to GABA agonists. An example of a partial inverse agonist is Ro15-4513. Subtype selective ligands A useful property of the many benzodiazepine receptor ligands is that they may display selective binding to particular subsets of receptors comprising specific subunits. This allows one to determine which GABAA receptor subunit combinations are prevalent in particular brain areas and provides a clue as to which subunit combinations may be responsible for behavioral effects of drugs acting at GABAA receptors. These selective ligands may have pharmacological advantages in that they may allow dissociation of desired therapeutic affects from undesirable side effects. Few subtype selective ligands have gone into clinical use as yet, but some examples of these compounds which are widely used in scientific research are Bretazenil (subtype-selective partial agonist), Imidazenil (partial agonist at some subtypes, weak antagonist at others) and QH-ii-066 (full agonist highly selective for α5 subtype). See also *GABA receptor *GABAB receptor *GABAC receptor *Glycine receptor References External links * * * Category:Transmembrane receptors